Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic ...instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on ...analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood ...eosinophil count and prospective annual asthma outcomes for a large UK cohort.
This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541.
Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio RR 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less.
Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment.
Teva Pharmaceuticals.
This review outlines a conceptual approach to inform research and practice aimed at supporting children whose lives are complicated by impairment and/or chronic medical conditions, and their ...families. ‘Participation’ in meaningful life activities should be an essential intervention goal, to meet the challenges of healthy growth and development, and to provide opportunities to help ensure that young people with impairments reach their full potential across their lifespan. Intervention activities and research can focus on participation as either an independent or dependent variable. The proposed framework and associated hypotheses are applicable to children and young people with a wide variety of conditions, and to their families. In taking a fresh ‘non‐categorical’ perspective to health for children and young people, asking new questions, and exploring issues in innovative ways, we expect to learn lessons and to develop creative solutions that will ultimately benefit children with a wide variety of impairments and challenges, and their families, everywhere.
What this paper adds
An innovative conceptual framework to support participation‐based research and practice.
Recommendations for future participation‐based research.
Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth.
We ...initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic.
We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65).
Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users.
The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to ...identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.
Display omitted
•A therapeutics resource identifies cancer genotype-compound sensitivity relationships•Genetic features of cancer cell lines correlate with their response to compounds•The resource controls for possible confounding factors of genomic cell-line profiling•Results suggest a strategy for treating cancers with mutations in β-catenin
The Cancer Therapeutics Response Portal catalogs the sensitivity of more than 200 cancer cell lines to specific small molecules. This resource should accelerate the development of individualized therapies tailored to specific cancers and patients.
We study the stellar mass functions (SMFs) of star-forming and quiescent galaxies in 11 galaxy clusters at 1.0 <
z
< 1.4 drawn from the Gemini Observations of Galaxies in Rich Early ENvironments ...(GOGREEN) survey. Based on more than 500 h of Gemini/GMOS spectroscopy and deep multi-band photometry taken with a range of observatories, we probe the SMFs down to a stellar mass limit of 10
9.7
M
⊙
(10
9.5
M
⊙
for star-forming galaxies). At this early epoch, the fraction of quiescent galaxies is already highly elevated in the clusters compared to the field at the same redshift. The quenched fraction excess (QFE) represents the fraction of galaxies that would be star-forming in the field but are quenched due to their environment. The QFE is strongly mass dependent, and increases from ∼30% at
M
⋆
= 10
9.7
M
⊙
to ∼80% at
M
⋆
= 10
11.0
M
⊙
. Nonetheless, the shapes of the SMFs of the two individual galaxy types, star-forming and quiescent galaxies, are identical between cluster and field to high statistical precision. Nevertheless, along with the different quiescent fractions, the total galaxy SMF is also environmentally dependent, with a relative deficit of low-mass galaxies in the clusters. These results are in stark contrast with findings in the local Universe, and therefore require a substantially different quenching mode to operate at early times. We discuss these results in light of several popular quenching models.
Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy ...measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.
This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank N=121,604 and 23andMe N=20,328) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).
The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (r
=0.76-0.92) and DSM-IV alcohol dependence (r
=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (r
=0.22), major depressive disorder (r
=0.26), and attention deficit hyperactivity disorder (r
=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (r
=-0.24) and ADHD (r
=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (r
=0.82) while retaining most subjects.
AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
Over the past two decades the primary driver of mass loss from the West Antarctic Ice Sheet (WAIS) has been warm ocean water underneath coastal ice shelves, not a warmer atmosphere. Yet, surface melt ...occurs sporadically over low-lying areas of the WAIS and is not fully understood. Here we report on an episode of extensive and prolonged surface melting observed in the Ross Sea sector of the WAIS in January 2016. A comprehensive cloud and radiation experiment at the WAIS ice divide, downwind of the melt region, provided detailed insight into the physical processes at play during the event. The unusual extent and duration of the melting are linked to strong and sustained advection of warm marine air toward the area, likely favoured by the concurrent strong El Niño event. The increase in the number of extreme El Niño events projected for the twenty-first century could expose the WAIS to more frequent major melt events.
Obtaining unbiased survey data for vocal bird species is inherently challenging due to observer biases, habitat coverage biases, and logistical constraints. We propose that combining bioacoustic ...monitoring with unmanned aerial vehicle (UAV) technology could reduce some of these biases and allow bird surveys to be conducted in less accessible areas. We tested the feasibility of the UAV approach to songbird surveys using a low-cost quadcopter with a simple, lightweight recorder suspended 8 m below the vehicle. In a field experiment using playback of bird recordings, we found that small variations in UAV altitude (it hovered at 28, 48, and 68 m) didn't have a significant effect on detections by the recorder attached to the UAV, and we found that the detection radius of our equipment was comparable with detection radii of standard point counts. We then field tested our equipment, comparing songbird detections from our UAV-mounted recorder with standard point-count data from 51 count stations. We found that the number of birds per point on UAV counts was comparable with standard counts for most species, but there were significant underestimates for some—specifically, issues of song masking for a species with a low-frequency song, the Mourning Dove (Zenaida macroura); and underestimation of the abundance of a species that was found in very high densities, the Gray Catbird (Dumetella carolinensis). Species richness was lower on UAV counts (mean = 5.6 species point−1) than on standard counts (8.3 species point−1), but only slightly lower than on standard counts if nonaudible detections are omitted (6.5 species point−1). Excessive UAV noise is a major hurdle to using UAVs for bioacoustic monitoring, but we are optimistic that technological innovations to reduce motor and rotor noise will significantly reduce this issue. We conclude that UAV-based bioacoustic monitoring holds great promise, and we urge other researchers to consider further experimentation to refine techniques.
PDF
